Suppression of tumor growth through disruption of hypoxia-inducible transcription.

Abstract

Chronic hypoxia, a hallmark of many tumors, is associated with angiogenesis and tumor progression. Strategies to treat tumors have been developed in which tumor cells are targeted with drugs or gene-therapy vectors specifically activated under hypoxic conditions. Here we report a different approach, in which the normal transcriptional response to hypoxia is selectively disrupted. Our data indicate that specific blockade of the interaction of hypoxia-inducible factor with the CH1 domain of its p300 and CREB binding protein transcriptional coactivators leads to attenuation of hypoxia-inducible gene expression and diminution of tumor growth. Thus, disrupting the normal co-activational response to hypoxia may be a new and useful therapeutic strategy.

• Authors: A L Kung, S Wang, J M Klco, W G Kaelin, D M Livingston
• Journal: Nature medicine (Nat Med) Vol. 6 Issue 12 Pg. 1335-40 (Dec 2000) ISSN: 1078-8956 [Print] United States
• PMID: 11100117 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nuclear Proteins
• Trans-Activators
• Transcription Factors
• CREB-Binding Protein
• Crebbp protein, mouse
• E1A-Associated p300 Protein
• Ep300 protein, mouse

Topics

• Animals
• Binding Sites
• CREB-Binding Protein
• Cell Hypoxia (genetics)
• DNA-Binding Proteins (metabolism)
• E1A-Associated p300 Protein
• Gene Expression Regulation, Neoplastic
• Genetic Therapy (methods)
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Mice
• Mice, Nude
• Neoplasms, Experimental (therapy)
• Neovascularization, Pathologic
• Nuclear Proteins (metabolism)
• Protein Binding
• Trans-Activators (metabolism)
• Transcription Factors
• Transcription, Genetic